Original article Discovering some novel tetrahydroquinoline derivatives bearing the biologically active sulfonamide moiety as a new class of antitumor agents Saleh I. Alqasoumi a , Areej M. Al-Taweel a , Ahmed M. Alafeefy b , Mostafa M. Ghorab c, * , Eman Noaman d a Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia c Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia d Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Nasr City, Cairo, Egypt article info Article history: Received 23 June 2009 Received in revised form 5 January 2010 Accepted 11 January 2010 Available online 20 January 2010 Keywords: Antitumor activity Tetrahydroquinoline Sulfonamide Synthesis abstract The present article describes the synthesis of some novel 4-(2-amino-3-cyano-4-(substituted-aryl)-5- oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfonamide (23–41) starting with 4-(3-oxo-cyclohex- 1-enylamino)benzenesulfonamide (3). All the newly synthesized compounds were evaluated for their in vitro antitumor activity. Compounds 32, 25, 41 , 35, 33, and 37 with IC 50 values (2.5, 3, 5, 10, 12, and 12.5 mg/mL) are more potent and efficacious than Doxorubicin (CAS-23214-92-8) as reference drug with (IC 50 value ¼ 37.5 mg/mL). Also, compounds 28, 30, 31 , and 34 (with IC 50 values ¼ 25 mg/mL) are nearly as active as Doxorubicin. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Protein tyrosine kinases (TKs) play an important role in cell growth and differentiation. These enzymes catalyze the transfer of a phosphate group from ATP to a tyrosine residue on an appropriate substrate, thereby bringing about cell signaling events. Several nonreceptor TKs have been identified, among them the Src family of cytoplasmic protein TKs [1]. The TK Src has been implicated in several disease states, including cancer [2,3], osteoporosis [4], and stroke [5]. Therefore, inhibition of Src kinase could prove useful in the treatment of these and other diseases. A number of Src family kinase inhibitors have been reported in the literature, including 4-anilinoquinazolines [6], pyrazolo [3,4-d]- pyrimidines [7], pyr- rolo[2,3-d]pyrimidines [8], pyrido[2,3-d ]pyrimidin-7(8H)-ones [9],1,6-naphthyridin-2(1H)-ones [10], and aminopyrido[2,3-d]pyr- imidin-7-yl ureas [11]. A series of 4-anilino-3-quinolinecarbonitrile compounds has been reported to be potent inhibitors of EGFr [12], Src [13] and MEK [14] kinases. While earlier synthetic efforts were directed at 4-anilino-6,7-dialkoxy-3-quinolinecarbonitrile Src kinase inhibitors, such as compound I [15], recent efforts have focused on 4-anilino-7-thienyl-3-quinolinecarbonitriles (e.g., II) as potent Src kinase inhibitors [16]. Given the obvious importance of quinoline-3-carbonitrile as efficient Src kinase inhibitors, and as part of our research effort to explore the new antitumor hetero- cyclic compounds [17–24], we synthesized a novel series of tetra- hydroquinoline-3-carbonitriles 23–41 , bearing the biologically active sulfonamide moiety at 1-position with substituted-aryl at the 4-position and free amino group at the 2-position as analogues of compounds I and II. 2. Results and discussion 2.1. Chemistry The present work reports the possible utility of 4-(3-oxo- cyclohex-1-enylamino)-benzenesulfonamide 3 in the synthesis of 4-(quinolin-1-yl)benzenesulfonamide derivatives 23–41 . Enami- none 3 was obtained by condensation of cyclohexan-1,3-dione 1 N O O HN CN O Cl Cl N HN CN O Cl Cl S N O CN NH 2 SO 2 NH 2 Ar I II N O N N 23-41 * Corresponding author. Tel.: þ966 534292860; fax: þ966 (01) 4670560. E-mail address: mmsghorab@yahoo.com (M.M. Ghorab). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.01.022 European Journal of Medicinal Chemistry 45 (2010) 1849–1853